Skip to main content

STORIES

Emerging Principal Investigators: Dr. Craig Smail

STORIES

Emerging Principal Investigators: Dr. Craig Smail

Headshot of Craig Smail, PhD
Craig Smail, PhD
Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Assistant Professor of Pediatrics, University of Kansas School of Medicine
Full Biography

As Children’s Mercy Research Institute (CMRI) grows its research programs, the institute has welcomed many innovative, early-career investigators to its roster of researchers. These investigators bring their novel ideas, unique talents, and diverse interests to CMRI. The following profile is one in our series on emerging principal investigators.

From a young age, Craig Smail, PhD, Research Faculty, Genomic Medicine Center, was fascinated by medicine. That fascination led him to a career in genetic research. He leads a computational research lab in the Genomic Medicine Center and is also an assistant professor at both the University of Missouri - Kansas City School of Medicine and the University of Kansas School of Medicine. “I find it very motivating to have the opportunity to discover new knowledge in medicine because it has the potential to impact patients and improve lives.” 

Dr. Smail joined CMRI in 2020 after finishing his PhD at Stanford University where he worked on rare diseases at the Stanford Center for Undiagnosed Diseases, a National Institutes of Health (NIH) Undiagnosed Disease Network site, under the mentorship of Stephen Montgomery, PhD. “I was interested in rare disease research, and the GA4K program at Children’s Mercy made it a top choice for me,” he said. Genomic Answers for Kids (GA4K) is a first-of-its-kind pediatric genetic data repository to facilitate research into pediatric genetic conditions.

Rare genetic variations and disease risk

Dr. Smail’s lab applies novel methods of computational and statistical analysis to the study of rare diseases and genetics. “My main research focus is understanding how rare human genetic variation affects disease risk,” he said. His lab uses large-scale functional profiles and long-read DNA-sequencing (a technique that uses longer DNA fragments than other methods for detection of complex variants), and patient-derived cell models. For development of the patient-derived cell models, his team collaborates with Scott Younger, PhD, Director, Disease Gene Engineering, Genomic Medicine Center. 

Dr. Smail explains that researchers had typically studied either rare variants in rare diseases or common variants in common diseases. “We're positioning ourselves in the middle of two worlds —rare disease genomics and common disease genomics— to push diagnostics further for rare disease patients,” he said. Currently, the rate of diagnosing people with rare disease remains around 40%. One explanation for undiagnosed rare disease is that only a subset of rare diseases has a single underlying variant, also known as a Mendelian variant.  “I think up to 50% of undiagnosed disease cases might be these non-Mendelian cases where there isn’t a single variant but a more complex kind of genetic underpinning to the disease,” Dr. Smail said. 

(L-R) Craig Smail, PhD; Cas LeMaster, MSC; Cory Yeager, Marissa Keever-Keigher, PhD

Pioneering methods in disease risk prediction

Dr. Smail’s lab has pioneered methods to integrate the effects of rare and common variants in complex disease risk prediction. Researchers use polygenic risk scores to quantify the effects of thousands to millions of common variants to assess risk for different diseases. He co-authored a paper in the American Journal of Human Genetics that outlined a model that combines common variant polygenic risk scores with a set of rare variants that were associated with gene dysregulation, which is an under-expression or over-expression of a gene compared to a healthy person. “We provided the first method for identifying and quantifying individual complex disease risk associated with rare variant burden linked to molecular dysregulation, showing decades-earlier onset for multiple common complex diseases and surgical corrective interventions such as in obesity and bariatric surgery,” he said.

NIH-funded projects

Dr. Smail is working on two NIH-funded projects. He is in the middle of a five-year, $1.9 million early-stage investigator award from the NIH National Institute of General Medical Sciences. “The project looks at how a rare disease might be explained through the combined effects of many common variants in addition to a single or burden of rare variants,” he said.

His second grant is a two-year, $429,000 R21 award from the NIH National Human Genome Research Institute. “The second grant looks at how we might be able to find rare variants with large trans-acting effects,” said Dr. Smail. “This effect is where a variant might cause profound impacts to a linked gene or genes, but where the variant is far away from those genes or even on different chromosomes.”

In addition to his two NIH grant projects, Dr. Smail is a co-investigator on Dr. Venkatesh Sampath’s NIH R01 grant on necrotizing enterocolitis in premature infants. 

When looking towards the future, Dr. Smail commented that his current projects will drive the direction of future work. “We will continue to build on our successes, and we are always interested in recruiting new lab members who work in computational and genomics research,” he said.